Celiac Disease
Celiac disease is an acquired chronic immune disorder that develops in susceptible individuals (many of whom are of HLA genotype DQ2 or DQ8) related to an environmental factor, gluten, which is the storage protein of wheat and related grains like rye and barley. The gluten-induced small bowel pathology in celiac disease is characterized by an inflammatory reaction that is accompanied by villus atrophy and hypertrophy of crypts. Celiac disease has a wide range of clinical manifestations including latent or silent celiac disease, disease with only mild gastrointestinal disturbances, chronic gastrointestinal symptoms, malabsorption, and/or weight loss. Celiac disease is often diagnosed in patients with isolated iron deficiency anemia.
The ingestion of gluten-containing cereals can also induce manifestations outside the gut, such as osteoporosis, peripheral and central nervous system involvement, mild or severe liver disease, infertility problems, and the classical example is the gluten-induced skin disease, dermatitis herpetiformis (DH). DH is a cutaneous manifestation of celiac disease in which an intensely pruritic, herpetiform rash can present on the elbows, knees, buttocks, and scalp of a celiac disease patient in response to ingestion of gluten. The rash is characterized by high IgA deposits seen histologically in the upper papillary dermis. The symptoms and histology of the rash improve with adherence to a gluten free diet. Approximately 10% of patients diagnosed with celiac disease will manifest DH.
The only accepted standard for celiac disease diagnosis is the finding of gluten-induced small intestinal mucosal injury. Clinical findings are usually equivocal: newly diagnosed patients eating normal gluten-containing food may be totally symptomless or have only vague gastrointestinal symptoms, whereas in others symptoms may be severe; in people with extra-intestinal manifestations, gastrointestinal symptoms may also be absent. One feature that is common to all however is the manifest gluten-sensitive small intestinal mucosal lesion. In untreated celiac disease, the length of functionally impaired bowel determines the degree of malabsorption, and the presence of symptoms does not relate at all to the histological features of the proximal biopsy. During the last two decades, highly sensitive and specific gluten-dependent serum autoantibody tests have been used for celiac disease case finding, population-based screening studies, monitoring the gluten-free diet, and measurement of mucosal relapse on gluten challenge.
For patients with celiac disease, lifelong complete gluten exclusion needs to be followed strictly to avoid a substantially enhanced risk for the development of further complications, such as bone disorders, infertility, and cancer. The mortality rate in patients with celiac disease exceeds that of the general population; however, there is a trend towards reduction in mortality after 1-5 years on a gluten-free diet.
Following a completely gluten-free diet is, however, very challenging. Even highly motivated patients who try to maintain a strict dietary regimen are affected due to inadvertent or background exposure to gluten (FDA 2006). As many as 80% of patients with celiac disease who are in clinical remission, and who claim to be following a gluten-free diet, have persistent abnormalities in small bowel biopsy specimens. Inadvertent exposure to gluten has been identified as the leading cause of non-responsive celiac disease among clinically diagnosed patients who were presumed to be on a gluten-free diet. A gluten-free diet is more expensive than a so-called ‘normal’ diet, which can make adherence to the diet difficult; also social life and travel contribute to dietary lapses. Taken together, there is an acute need for non-dietary therapies for celiac disease.
Time-course studies of gluten challenges provide clear evidence of an inflammatory process, as there is a dose-dependent accumulation of lymphocytes to the epithelium during the lower-dose gluten challenges. Upon further challenge, crypt hyperplasia occurs, and lastly, villus effacement is seen (flat mucosal lesion). As evidenced in clinical practice with patients having silent celiac disease, the mucosal deterioration upon gluten challenge is often seen before clinical symptoms occur. In one study challenging adolescent and young adult celiac patients with 10 g of gluten per day, a control small intestinal biopsy at the time of seroconversion of the celiac-type autoantibodies showed that the gut mucosa relapsed in 70% of the patients before clinical symptoms occurred. Thus, gluten-induced damage in the small intestinal mucosa is a prerequisite for symptoms and complications of celiac disease, some of which may occur only years or decades after starting gluten ingestion.
In celiac disease, the onset of symptoms and signs of gluten intolerance may occur in childhood but become evident only in adulthood or in the elderly after decades of gluten ingestion. People eating an average Western diet ingest approximately 15-25 g gluten per day. Previous clinical gluten challenge studies show that older children, adolescents, and young adults with long-term treated celiac disease can tolerate well the ingestion of 10-20 g gluten per day. Also, a gluten challenge with repeated small intestinal mucosal biopsies has until fairly recently been mandatory to establish the definite diagnosis of celiac disease, especially in children (in some parts of the world this regimen is still followed). The effect of small gluten loads on the mucosal integrity and a safe gluten threshold in treated celiac disease is still under discussion. The literature indicates that doses of 1.5 to 2 g of gluten per day should cause some deterioration and inflammation but without inducing too many clinical symptoms and causing severe side effects. One and a half grams to 2 g of daily gluten exposure corresponds to the ingestion of approximately one-half to two-thirds a slice of wheat flour-based bread per day. A drug, to be clinically effective, should be able to reduce significantly or prevent the mucosal deterioration caused by a daily gluten challenge.
The only currently available treatment option for celiac disease patients is complete exclusion of dietary gluten; however, because gluten is found ubiquitously in the food supply, strict avoidance is extraordinarily difficult if not impossible for most patients. Because of ongoing gluten exposure, celiac disease patients (even when attempting to adhere to a gluten-free diet) suffer from the consequences of continued gluten exposure, including a significant increase in associated morbidity and mortality. Taken together, these observations establish that celiac disease represents a serious unmet medical need; therefore, a therapeutic intervention that could serve as an adjunct to an attempted gluten-free diet to attenuate or eliminate the pro-inflammatory, immunogenic potential of gluten in celiac disease patients would be a major clinical advance in the treatment of this disease. The ultimate goal in celiac disease clinical research is to prevent disease and sustain health and to provide new therapeutic strategies that are less burdensome than a strict life-long gluten-free diet. A long term goal is a therapy that would allow celiac disease patients to be able to ingest foods containing wheat, barley, and/or rye safely. A drug for the treatment of celiac disease should be able to prevent gluten-induced mucosal injury. Only then will celiac experts, advisors for celiac support groups, and patient organizations, accept the drug as an adjunct therapy or alternative treatment to strict gluten-free diet.
Proteases for the Treatment of Celiac Disease
A promising new approach to treating celiac disease involves the oral administration of proteases, called glutenases, which can degrade gluten. See PCT Pat. Pub. No. 2003/068170; 2005/107786; 2007/044906; 2007/047303; 2008/115411; 2010/021752; and 2013/016427; and U.S. Pat. Nos. 7,303,871; 7,320,788; 7,628,985; 7,910,541; and 7,943,312, each of which is expressly incorporated herein by reference.
Cysteine endoprotease (EP) B2 (also known as EPB2), a barley derived protease, and other similar proteases derived from the germinating seeds of the gluten-containing cereals have been identified as effective agents for the detoxification of gluten, the causative agent in celiac disease (see U.S. Pat. Nos. 7,303,871 and 7,320,788; U.S. Pat. App. Pub. Nos. 20100092451 and 20110171201; and PCT Pub. 2013/016427). A modified, recombinant form of the barley-derived EPB2 zymogen called “ALV001” (the active form of this enzyme is termed “ALV001*” herein) has been used as part of a combination enzyme therapy (including a prolyl endopeptidase (PEP), such as Sphingomonas capsulata PEP) for oral administration to celiac disease patients to aid in the digestion of gluten before it can exert its toxic effects in these patients (see U.S. Pat. No. 7,320,788; U.S. Pat. App. Pub. No. 20080193436; PCT Patent Pub. Nos. 2008/115428; 2008/115411; 2010/021752; 2010/042203 and 2013/016427, each of which is expressly incorporated herein by reference). The ALV001 zymogen becomes active (converts to ALV001*) below pH 5, but is not activated at a higher pH.
ALV003 is an especially promising new drug in clinical development that is a mixture of two glutenases: Sphingomonas capsulata prolyl endopeptidase and ALV001 (or ALV001*). See PCT Pat. Pub. Nos. 2005/107786; 2008/115428; 2008/115411; 2010/021752; 2010/042203; and 2013/016427, each of which is expressly incorporated herein by reference. Oral glutenases such as ALV003 help to proteolyze the immunoreactive gluten peptides present in food before they can trigger an immune response in the intestinal mucosa. There remains a need for new methods and pharmaceutical compositions that can be used to protect celiac disease patients and other individuals suffering from gluten intolerance from the harmful effects of inadvertent exposure to gluten and to make gluten ingestion safer for them. The present invention meets these needs.